16Prior genome-wide association studies have identified a melanoma-associated locus on 17 chr1q42.1 that encompasses a ~100 kb region spanning the PARP1 gene. eQTL analysis in 18 multiple cell types of melanocytic lineage consistently demonstrated that the 1q42.1 melanoma 19 risk allele (rs3219090, G) is correlated with higher PARP1 levels. In silico fine-mapping and 20 functional validation identified a common intronic indel, rs144361550 (-/GGGCCC, r 2 =0.947 21 with rs3219090) as displaying allele-specific transcriptional activity. A proteomic screen 22 identified RECQL as binding to rs144361550 in an allele-preferential manner. In human primary 23 melanocytes, PARP1 promotes cell proliferation and rescues BRAF V600E -induced senescence 24 phenotypes in a PARylation-independent manner. PARP1 also transforms TERT-immortalized 25 melanocytes expressing BRAF V600E . PARP1-mediated senescence rescue is accompanied by 26 transcriptional activation of melanocyte lineage survival oncogene, MITF, highlighting a new role 27 of PARP1 in melanomagenesis. 28 29To date, genome-wide association studies (GWAS) have identified twenty common, 30 genome-wide significant melanoma susceptibility loci [1][2][3][4][5][6][7][8][9] , most of which do not appear to be 31 explained by protein-coding variants. A subset of these loci harbor known pigmentation genes 32 that mediate melanoma-associated phenotypes such as eye, hair, and skin color. While several 33 loci harbor genes implicated in cancer, evidence directly linking common risk variants within 34 most of these loci to altered function of specific genes is lacking. 35MacGregor and colleagues initially identified a melanoma risk locus tagged by 36 rs3219090 on chromosome band 1q42.1 in an Australian case-control study at a near genome-37 wide level of significance (P = 9.3 x 10 -8 , OR = 0.87, protective allele A) 8 . The association has 38 since been replicated by multiple other studies 3,10 , including most recently by a meta-analysis of 39 12,874 melanoma cases (rs1858550, P = 1.7 x 10 -13 ) 7 . Notably, the locus at 1q42.1 has also 40 been associated with melanoma survival 11 , where the melanoma risk allele correlates with 41 increased survival, an association that has since been replicated 12 . The region of association 42 spans from 226.52 Mb to 226.63 Mb (hg19) of chromosome 1, encompassing the entirety of the 43 poly(ADP-ribose) (PAR) polymerase-1 (PARP1) (OMIM: 173870) gene, and fine-mapping 44 suggests that the association is best explained by a single-SNP model 3 . 45While a number of other genes are located in the vicinity of the association peak, PARP1 46 has the most well-established role in cancer. PARP1 is best known for its role as a DNA repair 47 enzyme and genotoxic sensor that functions in base excision repair (BER), single-strand break 48 repair, and double-strand break repair , and appear to play a role in oncogene-induced senescence (OIS) 20,21 . 56Aside from DNA repair, PARP1 functions in regulating gene expression by modif...